PROJECT SUMMARY (ABSTRACT) Distant metastasis is the cause of most cancer deaths. This is particularly true for pancreatic cancer. These patients develop hundreds to thousands of metastases that appear suddenly and progress rapidly to fill the liver and lungs. This stage of the disease is rapidly lethal, poorly understood, and grossly understudied. Long-term Objectives: Characterize what drives and/or accelerates the metastatic stage of pancreatic cancer in patients, and use this knowledge to design new and effective treatment strategies. Research Design: This proposal is designed to deeply characterize how a metabolic enzyme named PGD drives pancreatic cancer metastasis. We recently discovered that sugar (glucose) activates PGD, and once PGD is activated it strongly stimulates metastatic tumor growth. Understanding how cancer cells use glucose to activate PGD and how PGD then promotes tumor growth is important: it could lead to the first effective treatment strategies against the most common and most lethal stage of disease progression. Research Methods: Experiments will use a powerful set of metastatic pancreatic cancer cells and tissues that were collected from individual patients who died of the disease. Unique three-dimensional experimental platforms will allow us to investigate how these cancers learned to form metastatic tumors in the patients. Experiments will specifically focus on how the metastatic cells process glucose into metabolites that activate the PGD enzyme, and how the activated PGD enzyme is then able to enhance metastatic tumor growth. Aim 1: Determine how glucose fuels high PGD catalytic activity in distant metastases. Aim 1 will investigate how an unusual series of metabolic reactions convert glucose into metabolites that activate PGD. Our recent work was the first to detect these reactions in humans. That is because they are only operational in the metastatic cancer cells. Their function is to support PGD-driven metastasis. Aim 2: Define the mechanism whereby PGD is constitutively activated in distant metastases. Aim 2 will investigate how activated PGD is able to accelerate the rates of both glucose consumption and fatty acid biosynthesis in the metastatic cancer cells. This not only strongly promotes metastatic tumor growth, but also maintains PGD in a perpetually activated state that cannot be switched off in the presence of glucose. Aim 3: Investigate how PGD reprograms the epigenome to activate the metastatic transcriptome. Aim 3 will investigate how PGD is able to control the ?epigenome?, which refers to small chemical modifications within chromatin that regulate expression of the genes encoded in the DNA sequence (the ?transcriptome?). PGD reprograms the pancreatic cancer epigenome by accelerating glucose consumption. The metastatic cells break the extra glucose down into the smaller epigenetic chemicals. The chemicals are then used to increase expression of numerous genes that enhance metastatic tumor growth and bestow treatment resistance.